AN ABSTRACT OF THE THESIS OF Dong Su for the degree of Master of Science in Chemistry presented on May 31, 2012. Title: Synthetic Studies Toward the Total Synthesis of Azaspiracid-1 Abstract approved:__________________________________________________ Rich G. Carter Azaspiracid-1, a novel marine toxin that contains 9 rings and 20 stereogenic centers, has drawn considerable attention from synthetic groups worldwide due to its structural complexity, which includes a unique trioxabisspiroketal fused to a tetrahydrofuran ring (ABCD rings), a piperidine-tetrahydrofuran spiroaminal system fused to a 2,9-dioxabicyclo[3.3.1]nonane system (FGHI rings), a connecting six-membered cyclic hemiketal bridge (E ring) and a γ,δ-unsaturated terminal carboxylic acid side chain. Our efforts toward the total synthesis of azaspiracid-1 led to the completion of both C1-C26 northern and C27-C40 southern halves of azaspiracid-1. Herein, our improved and scalable synthetic studies toward the total synthesis of azaspiracid-1 is described. In particular, an improved and scalable synthesis of sulfone 3.6 with a key one-pot ketalization and methylation of ketone 3.22 to methylated hemiketal 3.24 is illustrated. A total 19 mmol of sulfone 3.6 has been prepared by this approach. An improved and scalable synthesis of aldehyde 3.7 utilizing allyl bromide 3.31 to couple with Evans auxiliary 3.33 has been developed. A total of 10 mmol of aldehyde 3.7 has been prepared by this approach. An improved synthesis toward the ABC ring fragment 3.52 with a high yield Julia coupling step is shown. Large scale improved syntheses of the linkage fragment 3.2, the aldehyde fragment 4.9 and the azide fragment 4.10 of the southern portion of (–)-azaspiracid- 1 have been described. With an abundant material prepared by this scalable improved approach, we are confident that completing the total synthesis of (–)-azaspiracid-1 will occur in the near future. ©Copyright by Dong Su May 31, 2012 All Rights Reserved Synthetic Studies Toward the Total Synthesis of Azaspiracid-1 by Dong Su A THESIS submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science Presented on May 31, 2012 Commencement June, 2013 Master of Science thesis of Dong Su presented on May 31, 2012. APPROVED: __________________________________________________________________ Major Professor, representing Chemistry __________________________________________________________________ Chair of the Department of Chemistry __________________________________________________________________ Dean of the Graduate School I understand that my thesis will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my thesis to any reader upon request. __________________________________________________________________ Dong Su, Author ACKNOWLEDGEMENTS I would like to thank Professor Rich G. Carter for his support, guidance, encouragement, inspiration and friendship that he extended throughout my graduate studies in Oregon State University. I really appreciate the opportunities he gave me to work on this exciting project. His mentorship plays an important role in my career development. I would like to thank my committee members, Prof. Paul R. Blakemore, Prof. Christopher M. Beaudry, Prof. Douglas A. Keszler and Prof. John Simonsen for their helpful advice and help. Additionally, I would like to thank all the members of Carter research group for their help and friendship during the last two and half years. I would like to thank my parents who have contributed so much to my education and whose love and support have been so important to my life. I would also thank my four sisters whose love and care means so much to my career. I would like to thank all the Chinese friends in Oregon State University who have made my life here a very good time, particular thanks to FangYuan Han, Chong Fang, Wei Wang couple, WeiMin Liu, Cheng Li etc. I would like to thank Roger Kohnert for his advice and guidance with NMR spectroscopy I would like to thank National Institute of Health and the Chemistry Department of Oregon State University for financial support. TABLE OF CONTENTS Page CHAPTER 1: Introduction of Spiroketals .................................................................1 1.1 Spiroketal Natural Products .................................................................................2 1.2 Conformations of Natural Spiroketals .................................................................6 1.2.1 Anomeric Effect ................................................................................................6 1.2.2 Conformations of Dioxaspiralketals .................................................................8 1.2.3 Conformations of Trioxaspiralketals.................................................................9 1.2.4 Conformation of Naturally Occuring Spiroketals ...........................................14 1.2.5 Summary .........................................................................................................17 1.3 Acid-Catalyzed Spirocyclization and Spiroisomerization. ................................17 1.3.1 Conformational Effects on Spiroketal Reactivity. ..........................................18 1.3.2 Acid-Catalyzed Spiroisomerization. ...............................................................18 1.3.3 Synthesis of Spiroketals by Acid-Catalyzed Spirocyclization. .......................20 1.4 Conclusion..........................................................................................................25 TABLE OF CONTENTS (Continued) Page 1.5 References. .........................................................................................................26 CHAPTER 2: Background of Azaspiracid-1 ...........................................................32 2.1 Discovery, Isolation and Bioactivities of Azaspiracid-1 ....................................33 2.2 Original Structural and Revised Structure of Azaspiracid-1..............................35 2.3 Synthetic Efforts Toward Azaspiracid-1 ............................................................40 2.3.1 Nicolaou’s First Generation Total Synthesis of (-)-azaspiracid-1 ..................40 2.3.2 Nicolaou’s Second Generation Total Synthesis of (-)-azaspiracid-1 ..............49 2.3.3 Evans’ Total Synthesis of (+)-azaspiracid-1 ...................................................50 2.3.4 The Carter Group synthetic studies toward azaspiracid-1 ..............................60 2.3.5 The Forsyth Group synthetic studies toward azaspiracid-1 ............................64 2.3.6 The Sasaki Group synthetic studies toward azaspiracid-1 ..............................67 2.3.7 The Mootoo Group synthetic studies toward azaspiracid-1 ............................68 2.4 Conclusion..........................................................................................................70 TABLE OF CONTENTS (Continued) Page 2.5 Reference............................................................................................................71 CHAPTER 3: Synthetic Studies on the Northern ABCD ring system of Azaspiracid-1: An Improved Synthesis of the sulfone fragment 3.6, the aldehyde fragment 3.7 and the ABC ring Bisspiroketal Moiety 3.52 .....77 3.1 Retrosynthesis of (-)-Azaspiracid-1. ..................................................................77 3.2 Synthetic studies toward the synthesis of the northern portion ABCD ring system 3.1. ...............................................................................................79 3.2.1 Synthesis of sulfone 3.6 ..................................................................................80 3.2.2 Synthesis of aldehyde 3.7 ................................................................................88 3.2.3 synthesis of the ABC ring Bisspiroketal Moiety 3.52 (Scheme 3.11) ............93 3.3 Conclusion..........................................................................................................96 3.4 Reference............................................................................................................96 TABLE OF CONTENTS (Continued) Page CHAPTER 4: Synthetic Studies on the Southern Half and the Linkage fragment of Azaspiracid-1: An Improved Synthesis of the Linkage Fragment 3.2, the Aldehyde Fragment 4.9 and the Azide Fragment 4.10 of Azaspiracid-1 98 4.1 An Improved Synthesis of the Linkage Fragment 3.2 .......................................99 4.2 Synthetic Studies on the Southern Portion of Azaspiracid-1 ...........................100 4.2.1 Retrosynthetic Analysis of the Southern Portion Fragment 3.3 ....................100 4.2.2 An Improved Synthesis of Aldehyde Fragment 4.9 of the Southern Portion ...............................................................................................................101 4.2.3 An Improved Synthesis of Azide Fragment 4.10 of the Southern Portion ...105 4.3 Conclusion........................................................................................................105 4.4 Future work ......................................................................................................106 4.5 Reference..........................................................................................................109 CHAPTER 5: Experimental Section ......................................................................110 LIST OF FIGURES Figure Page Figure 1.1. Structures of milbermycins, avermectins and ivermectin. .......................3